Letter pubs.acs.org/OrgLett
Nickel-Catalyzed Reductive Methylation of Alkyl Halides and Acid Chlorides with Methyl p‑Tosylate Zhuye Liang,†,§ Weichao Xue,‡,§ Kunhua Lin,*,‡ and Hegui Gong*,‡ †
College of Chemistry and Molecular Engineering, Zhengzhou University, 100 Science Road, Zhengzhou 450001, China Department of Chemistry, Shanghai University, 99 Shang-Da Road, Shanghai 200444, China
‡
S Supporting Information *
ABSTRACT: Methylation of unactivated alkyl halides and acid chlorides under Ni-catalyzed reductive coupling conditions led to efficient formation of methylated alkanes and ketones using methyl p-methyl tosylate as the methylation reagent. Moderate to excellent coupling yields as well as excellent functional group tolerance were observed under the present mild and easy-to-operate reaction conditions.
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Scheme 1. Ni-catalyzed Reductive Coupling of Alkyl Halides with Methyl p-Tosylate
ethyl groups are the smallest carbon substituents that play important roles in many medicinal compounds such as in the top-selling drug Seretide1 and in materials such as poly(methyl methacrylate) and poly(propylene oxide)s.2 In addition to the conventional coupling of methyl halides with alkyl or aryl metallic reagents,3 methylation on aryl and alkyl carbons can also be realized via transition-metal-catalyzed coupling of Me-metallic nucleophiles with organoelectrophiles.4−6 Therein, the methyl and more hindered alkyl nucleophiles generally illustrate similar reactivities in the C−C bond-forming process. For instance, Jarvo reported that methylation of chiral benzylic ethers led to asymmetric production of benzylic methanes, which can be extended to more sterically bulky alkyl groups.5 Another notable protocol to benzyl-Me compounds disclosed by Shi emphasizes the reaction of benzyl alcohol with Me.6 Recently, methylation of aryl carbons can also be accessed through aryl C−H bond activation protocols.7 Methylation via C−H activation of sp3 carbons is also disclosed; however, it was often a constraint to directing group-assisted Pd-catalyzed methods.8 In light of the recent development of nickel-catalyzed reductive coupling of alkyl electrophiles with other electrophiles that have been disclosed by us and others,9−13 we reasoned that direct coupling of methyl electrophiles with other organo halides would provide a more straightforward means to methylated products. Interestingly, methylation of other electrophiles with methyl electrophiles under the well-developed reductive coupling conditions has not been revealed (Scheme 1, eq 1). This is possibly due to rapid dimerization or hydrodehalogenation of the most accessible methyl electrophile source, e.g., MeI. Indeed, investigation of the coupling of MeI with aryl, allyl, and alkyl electrophiles proved to be ineffective under the Nicatalyzed, zinc-mediated reductive coupling conditions that have been developed from our laboratory for unactivated alkyl halides.9 Previously, we have developed an efficient cross-coupling of two unactivated alkyl halides by employing bis(pinacolato)diboron as the terminal reductant, in which only 1.5 equiv of © XXXX American Chemical Society
primary bromides was employed for coupling with secondary bromides.14 Meanwhile, we examined the coupling of 4-bromo1-tosylpiperidine (1) with n-heptyl tosylate, which delivered the desired product in a low yield.14 The formation of a C(sp3)− C(sp3) bond using primary alkyl tosylate suggests that it might be possible to develop an efficient method for methylation of alkyl halides with methyl tosylate, wherein the distinctive reactivity of methyl tosylate may allow the nickel catalyst to effectively bias the two coupling partners. Herein, we describe the achievement of this objective, specifically, nickel-catalyzed coupling of methyl p-toluenesulfonate with alkyl bromides, that occurs under very mild conditions as shown in eq 2 (Scheme 1). In addition, reductive alkylation of acid chlorides with MeOTs was also investigated and proved to be effective. At the outset, the reaction conditions for Ni-catalyzed reductive coupling of two alkyl electrophiles (alkyl ≠ Me) was tested for the coupling of MeOTs with 1.14 The desired product 2 was obtained in a trace amount (Table 1, entry 1). However, under similar conditions using NiCl2·glyme as the precatalyst, compound 2 was obtained in 56% yield (entry 2). Use of 2 equiv of MeOTs resulted in a lower yield (entry 3). Further Received: September 11, 2014
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Table 1. Optimization for the Coupling of 1 and MeOTs
entrya
catalyst
ligand
solvent
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
NiI2 NiCl2·glyme NiCl2·glyme NiCl2·glyme NiCl2·glyme NiCl2·glyme NiCl2·glyme NiCl2·glyme NiCl2·glyme NiCl2·glyme NiBr2·diglyme Ni(COD)2 NiCl2·glyme NiCl2·glyme NiCl2·glyme
3a 3a 3a 3b 3c 3d 4 5 6 7 5 5 5 5 5
NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP/iPr2O = 7:3 DMA/iPr2O = 7:3 NMP/MeCN = 7:3
6 56 47c 55 55 49 21 65 33 7 68 65 85 71 80
Scheme 2. Coupling of 1 with Other Methyl Sulfonates
a
Reaction conditions: 1 (100 mol %, 0.15 M in NMP), MeOTs (150 mol %), NiCl2·glyme (10 mol %), B2(Pin)2 (200 mol %), ligand (10 mol %), MeOLi (250 mol %), NMP (1 mL). bYields were determined by using GC−MS with 1-tosylpyrrolidine as an internal standard (calibrated). c2.0 equiv of MeOTs.
examination of the ligands, e.g., 3b−d and 4−7, indicated 5 (Figure 1) to be optimal (entries 4−10), generating 2 in 65%
Figure 2. Examples of methylation of various alkyl halides. (a) Isolated yields. (b) Yields were determined by 1H NMR analysis of an inseparable mixture of product and hydrodehalogenation byproduct using PhTMS as internal standard (calibrated). (c) The ratio of product to hydrodehalogenation byproduct was determined by 1H NMR analysis.
Figure 1. Structures of ligands.
yield (entry 8). With ligand 5, other Ni sources were generally inferior, except Ni(COD)2 and NiBr2·diglyme which gave 2 with comparable results (entries 11 and 12). Finally, extensive examination of solvents showed that a mixture of NMP/iPr2O in a ratio of 7:3 is optimal (entries 13−15), which gave rise to 2 in a best 85% yield (entry 13). Under the optimized conditions for 1, the iodo analogue, 4-iodo-1-tosylpiperidine, was less effective and only resulted in 2 in 64% yield. The employment of MeI in place of MeOTs led to a trace amount of product. Under the optimized reaction conditions, coupling of 1 with other sulfonates such as methyl phenylsulfonate, methyl methylsulfonate, and methyl trifluorosulfonate was inferior to MeOTs (Scheme 2). With the optimized reaction conditions being identified (Table 1, entry 13), we examined the scope of secondary and primary alkyl bromides (Figure 2). A variety of cyclic and openchain secondary and primary halides were competent with the
reductive coupling conditions, generally giving methylation products 9−18 in moderate to good yields, where a wide range of functional groups including ester, ketone, indole, phthalimide, and sterically dense 2-TBDPS-protected silyl ether are tolerated. 3-Methyl-1-tosylpyrrolidine 18 was also achieved in moderate yield, where the bromo substrate often suffers from a β-H elimination issue. The unprotected TsNH group underwent methylation on the nitrogen as evident in 19, which consequently resulted in a poor yield for 19. While the sterically more hindered primary alkyl bromides, e.g., 20, gave poor coupling yield, moderate to good yields for the methylation of less hindered primary bromides were generally observed, e.g., in 21−32. Interestingly, the Cbz-protected free amine did not undergo N-methylation as evident in 30. Again, excellent B
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formation of methyl-Zn reagent cannot be excluded, but it should not dominate the reaction process. The reason why MeOTs is suited for methylation is possibly due to relatively slow formation of MeX (X = Cl, Br arising from NiCl2 or alkyl bromides) under the conditions of methylation of alkyl halides and MeI in ketone formation, which avoids rapid dimerization of MeX (X = I, Cl, Br) due to their low concentrations. This hypothesis is in agreement with our previously proposed mechanisms for alkyl− alkyl (Ni/Bpin) and ketone-forming reactions.9b,14 The former case involves oxidative addition of first R1alkyl−X to Ni(I)−Bpin followed by reductive elimination of Bpin−X to give R1alkyl− Ni(I). Subsequent oxidative addition of R2alkyl−X to R1alkyl−Ni(I) gives R1alkyl−Ni(III)− R2alkyl, which delivers the product upon reductive elimination (Scheme 4).14 Successful cross-coupling of
functional group compatibility was observed for methylation of primary alkyl bromides including conjugated alkene as in 27. Similarly, with MeOTs being the methylation reagent, we examined the possibility of methylation of allylic carbonate, aryl bromide, and acid chlorides under the standard conditions developed by our laboratory (Scheme S1, Supporting Information).9b,d,e,15,16 Whereas the allyl and aryl electrophiles failed to generate methylation products (Scheme S1, Supporting Information), 4-Methoxy benzoyl chloride provided the desired ketone product in 27% yield in the presence of Bu4NI (Scheme S1, Supporting Information).16 Extensive optimization of the reaction parameters enabled us to boost the yield to 60% by using 15% of Ni(acac)2, 15% of 5,5′-dimethyl-2,2′-bipyridine (8), and 1.5 equiv of acid chlorides and MgCl2 in THF/CH3CN (v/v, 4:1) (Scheme 3).
Scheme 4. Proposed Catalytic Cycle for Methylation of Alkyl Halides
Scheme 3. Optimized Reaction Conditions for Methylation of 4-Methoxybenzoyl Chloride
Application of the optimized methyl ketone formation conditions to a variety of aryl acid chlorides were explored, generating 33−43. In general, the aryl rings bearing electrondonating substituents displayed better coupling efficiency than those containing electron-withdrawing groups by delivering moderate to good yields as evident in Figure 3. The use of methyl two alkyl halides would require a matched oxidative addition rates for the two coupling partners. Therefore, a low concentration of MeX (X = Cl, Br) should guarantee a low oxidative addition rate for MeX so as to match the oxidative addition rate for a second yet more hindered alkyl halide. Consequently, rapid dimerization of MeX can be avoided. For ketone synthesis, the proposed mechanism suggests that oxidative addition of acid chlorides to Ni(0) needs to be faster than that of MeX.9b A low concentration of MeX (X = I) is therefore pivotal to reduce the oxidative addition rate of MeX to Ni(0). In summary, we have identified methyl tosylate as an excellent methylation reagent for reductive coupling with unactivated alkyl halides and aryl acid chlorides, which allows efficiently installation of a methyl group for alkyl−methyl and ketone formation. The reactions avoid in situ formation of methyl zinc reagents which generally inhibit the reductive coupling process. The easy-to-operate and mild conditions may provide applications for preparation of compounds of interests.
Figure 3. Examples of methylation of various aryl acid chlorides. (a) Isolated yields. (b) Yields were determined by 1H NMR analysis using PhTMS as an internal standard (calibrated).
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4-(chlorocarbonyl)benzoate only resulted in a trace amount of ketone product 44. Finally, the alkyl acid, e.g., 3-phenylpropanoyl chloride, only provided the ketone 45 in low yield. In our previous studies, we have demonstrated that under the Ni/(Bpin)2 reductive coupling conditions in situ formation of alkyl-Bpin followed by Suzuki mechanism is not operative.14 Similarly, we have also illustrated that the coupling of alkyl-Zn reagents with aryl acid chlorides is a slower process than reductive coupling ketone formation.9c,b Indeed, while MeBpin did not give the coupling product, MeZnI was much less effective than MeOTs.16 Consequently, we believe that the present methylation of alkyl halides should not involve in situ formation of methyl-Bpin.17 In the reductive ketone-forming process, the
ASSOCIATED CONTENT
S Supporting Information *
Experimental procedures and analytical data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: [email protected]. *E-mail: [email protected]. Author Contributions §
Z.L. and W.X. contributed equally.
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Notes
2670. (b) Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674− 688. (c) Hu, X. Chem. Sci. 2011, 2, 1867−1886. (13) For recent reviews on reductive coupling of two electrophiles, see: (a) Knappke, C. E. I.; Grupe, S.; Gärtner, D.; Corpet, M.; Gosmini, C.; von Wangelin, A. J. Chem.Eur. J. 2014, 20, 6828−6842. (b) Everson, D. A.; Weix, D. J. J. Org. Chem. 2014, 80, 4793−4798. (c) Moragas, T.; Correa, A.; Martin, R. Chem.Eur. J. 2014, 20, 8242−8258. (14) Xu, H.; Zhao, C.; Qian, Q.; Deng, W.; Gong, H. Chem. Sci. 2013, 4, 4022−4029. (15) Lu, W.; Liang, Z.; Zhang, Y.; Wu, F.; Qian, Q.; Gong, H. Synthesis 2013, 45, 2234−2240. (16) See the Supporting Information for details. (17) For Ni-, Cu-, and Pd-catalyzed alkyl−Bpin formation, see: (a) Dudnik, A. S.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 10693−10697. (b) Yang, C.-T.; Zhang, Z.-Q.; Tajuddin, H.; Wu, C.-C.; Liang, J.; Liu, J.H.; Fu, Y.; Czyzewska, M.; Steel, P. G.; Marder, T. B.; Liu, L. Angew. Chem., Int. Ed. 2012, 51, 528−532. (c) Ito, H.; Kubota, K. Org. Lett. 2012, 14, 890−893. (d) Joshi-Pangu, A.; Ma, X.; Diane, M.; Iqbal, S.; Kribs, R. J.; Huang, R.; Wang, C.-Y.; Biscoe, M. R. J. Org. Chem. 2012, 77, 6629−6633. (e) Yi, J.; Liu, J. H.; Liang, J.; Dai, J. J.; Yang, C. T.; Fu, Y.; Liu, L. Adv. Synth. Catal. 2012, 354, 1685−1691.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Dr. Hongmei Deng (Shanghai University) is thanked for use of the NMR facility. Financial support was provided by the Chinese NSF (Nos. 21172140 and 21372151) and the Program for Professor of Special Appointment at Shanghai Institutions of Higher Learning (Dongfang Scholar) Shanghai Education Committee.
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REFERENCES
(1) Barreiro, E. J.; Kümmerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111, 5215−5246. (2) Peretti, K. L.; Ajiro, H.; Cohen, C. T.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2005, 127, 11566−11567. (3) (a) Takagi, M.; Nojima, M.; Kusabayashi, S. J. Am. Chem. Soc. 1983, 105, 4676−4684. (b) Ebert, G. W.; Rieke, R. D. J. Org. Chem. 1988, 53, 4482−4488. (4) For selected examples, see: (a) Fischer, C.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594−4595. (b) Nakamura, Y.; Yoshikai, N.; Ilies, L.; Nakamura, E. Org. Lett. 2012, 14, 3316−3319. (c) Whitesides, G. M.; Fischer, W. F., Jr.; San Filippo, J., Jr.; Bashe, R. W.; House, H. O. J. Am. Chem. Soc. 1969, 91, 4871−4882. (d) Imperato, G.; Vasold, R.; König, B. Adv. Synth. Catal. 2006, 348, 2243−2247. (e) Guan, B.-T.; Xiang, S.-K.; Wu, T.; Sun, Z.-P.; Wang, B.-Q.; Zhao, K.-Q.; Shi, Z.-J. Chem. Commun. 2008, 1437−1439. (5) (a) Wisniewska, H. M.; Swift, E. C.; Jarvo, E. R. J. Am. Chem. Soc. 2013, 135, 9083−9090. (b) Taylor, B. L. H.; Swift, E. C.; Waetzig, J. D.; Jarvo, E. R. J. Am. Chem. Soc. 2011, 133, 389−391. (c) Greene, M. A.; Yonova, I. M.; Williams, F. J.; Jarvo, E. R. Org. Lett. 2012, 14, 4293− 4296. (d) Yonova, I. M.; Johnson, A. G.; Osborne, C. A.; Moore, C. E.; Morrissette, N. S.; Jarvo, E. R. Angew. Chem., Int. Ed. 2014, 53, 2422− 2427. (e) Gong, H.; Sinisi, R.; Gagné, M. R. J. Am. Chem. Soc. 2007, 129, 1908−1909. (6) (a) Yu, D.-G.; Wang, X.; Zhu, R.-Y.; Luo, S.; Zhang, X.-B.; Wang, B.-Q.; Wang, L.; Shi, Z.-J. J. Am. Chem. Soc. 2012, 134, 14638−14641. (b) Guan, B.; Xiang, S.; Wang, B.; Sun, Z.; Wang, Y.; Zhao, K.; Shi, Z. J. Am. Chem. Soc. 2008, 130, 3268−3269. (7) (a) Zhang, Y.; Feng, J.; Li, C. J. J. Am. Chem. Soc. 2008, 130, 2900− 2901. (b) Thuy-Boun, P. S.; Villa, G.; Dang, D.; Richardson, P.; Su, S.; Yu, J.-Q J. Am. Chem. Soc. 2013, 135, 17508−17513. (8) Zhang, S.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G. J. Am. Chem. Soc. 2013, 135, 2124−2127. (9) (a) Yin, H.; Zhao, C.; You, H.; Lin, Q.; Gong, H. Chem. Commun. 2012, 48, 7034−7036. (b) Wu, F.; Lu, W.; Qian, Q.; Ren, Q.; Gong, H. Org. Lett. 2012, 14, 3044−3047. (c) Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Org. Lett. 2011, 13, 2138−2141. (d) Dai, Y.; Wu, F.; Zang, Z.; You, H.; Gong, H. Chem.Eur. J. 2012, 16, 808−812. (e) Wang, S.; Qian, Q.; Gong, H. Org. Lett. 2012, 14, 3352−3353. (10) For reductive coupling of C(sp3)−X with CO2, see: (a) Correa, A.; León, T.; Martin, R. J. Am. Chem. Soc. 2014, 136, 1062−1069. (b) Liu, Y.; Cornella, J.; Martin, R. J. Am. Chem. Soc. 2014, 136, 11212− 11215. (11) For selected examples of reductive coupling comprising alkyl halides, see: (a) Biswas, S.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 16192−16917. (b) Zhao, Y.; Weix, D. J. J. Am. Chem. Soc. 2014, 136, 48−51. (c) Everson, D. A.; Shrestha, R.; Weix, D. J. J. Am. Chem. Soc. 2010, 132, 920−921. (d) Goldup, S. M.; Leigh, D. A.; McBurney, R. T.; McGonigal, P. R.; Plant, A. Chem. Sci. 2010, 1, 383−386. (e) Qian, X.; Auffrant, A.; Felouat, A.; Gosimini, C. Angew. Chem., Int. Ed. 2011, 50, 10402−10405. (f) Wotal, A. C.; Weix, D. J. Org. Lett. 2012, 14, 1476− 1479. (g) Wotal, A. C.; Ribson, R. D.; Weix, D. J. Organometallics 2014, 33, 5874. (h) Liu, H.; Wei, J.; Qiao, Z.; Fu, Y.; Jiang, X. Chem.Eur. J. 2014, 20, 8308−8313. (12) For selected reviews on nickel-catalyzed couplings, see: (a) Rudolph, A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 2656− D
dx.doi.org/10.1021/ol502682q | Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Reductive Methylation of Alkyl Halides and Acid Chlorides with Methyl p‑Tosylate Zhuye Liang,†,§ Weichao Xue,‡,§ Kunhua Lin,*,‡ and Hegui Gong*,‡ †
College of Chemistry and Molecular Engineering, Zhengzhou University, 100 Science Road, Zhengzhou 450001, China Department of Chemistry, Shanghai University, 99 Shang-Da Road, Shanghai 200444, China
‡
S Supporting Information *
ABSTRACT: Methylation of unactivated alkyl halides and acid chlorides under Ni-catalyzed reductive coupling conditions led to efficient formation of methylated alkanes and ketones using methyl p-methyl tosylate as the methylation reagent. Moderate to excellent coupling yields as well as excellent functional group tolerance were observed under the present mild and easy-to-operate reaction conditions.
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Scheme 1. Ni-catalyzed Reductive Coupling of Alkyl Halides with Methyl p-Tosylate
ethyl groups are the smallest carbon substituents that play important roles in many medicinal compounds such as in the top-selling drug Seretide1 and in materials such as poly(methyl methacrylate) and poly(propylene oxide)s.2 In addition to the conventional coupling of methyl halides with alkyl or aryl metallic reagents,3 methylation on aryl and alkyl carbons can also be realized via transition-metal-catalyzed coupling of Me-metallic nucleophiles with organoelectrophiles.4−6 Therein, the methyl and more hindered alkyl nucleophiles generally illustrate similar reactivities in the C−C bond-forming process. For instance, Jarvo reported that methylation of chiral benzylic ethers led to asymmetric production of benzylic methanes, which can be extended to more sterically bulky alkyl groups.5 Another notable protocol to benzyl-Me compounds disclosed by Shi emphasizes the reaction of benzyl alcohol with Me.6 Recently, methylation of aryl carbons can also be accessed through aryl C−H bond activation protocols.7 Methylation via C−H activation of sp3 carbons is also disclosed; however, it was often a constraint to directing group-assisted Pd-catalyzed methods.8 In light of the recent development of nickel-catalyzed reductive coupling of alkyl electrophiles with other electrophiles that have been disclosed by us and others,9−13 we reasoned that direct coupling of methyl electrophiles with other organo halides would provide a more straightforward means to methylated products. Interestingly, methylation of other electrophiles with methyl electrophiles under the well-developed reductive coupling conditions has not been revealed (Scheme 1, eq 1). This is possibly due to rapid dimerization or hydrodehalogenation of the most accessible methyl electrophile source, e.g., MeI. Indeed, investigation of the coupling of MeI with aryl, allyl, and alkyl electrophiles proved to be ineffective under the Nicatalyzed, zinc-mediated reductive coupling conditions that have been developed from our laboratory for unactivated alkyl halides.9 Previously, we have developed an efficient cross-coupling of two unactivated alkyl halides by employing bis(pinacolato)diboron as the terminal reductant, in which only 1.5 equiv of © XXXX American Chemical Society
primary bromides was employed for coupling with secondary bromides.14 Meanwhile, we examined the coupling of 4-bromo1-tosylpiperidine (1) with n-heptyl tosylate, which delivered the desired product in a low yield.14 The formation of a C(sp3)− C(sp3) bond using primary alkyl tosylate suggests that it might be possible to develop an efficient method for methylation of alkyl halides with methyl tosylate, wherein the distinctive reactivity of methyl tosylate may allow the nickel catalyst to effectively bias the two coupling partners. Herein, we describe the achievement of this objective, specifically, nickel-catalyzed coupling of methyl p-toluenesulfonate with alkyl bromides, that occurs under very mild conditions as shown in eq 2 (Scheme 1). In addition, reductive alkylation of acid chlorides with MeOTs was also investigated and proved to be effective. At the outset, the reaction conditions for Ni-catalyzed reductive coupling of two alkyl electrophiles (alkyl ≠ Me) was tested for the coupling of MeOTs with 1.14 The desired product 2 was obtained in a trace amount (Table 1, entry 1). However, under similar conditions using NiCl2·glyme as the precatalyst, compound 2 was obtained in 56% yield (entry 2). Use of 2 equiv of MeOTs resulted in a lower yield (entry 3). Further Received: September 11, 2014
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Table 1. Optimization for the Coupling of 1 and MeOTs
entrya
catalyst
ligand
solvent
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
NiI2 NiCl2·glyme NiCl2·glyme NiCl2·glyme NiCl2·glyme NiCl2·glyme NiCl2·glyme NiCl2·glyme NiCl2·glyme NiCl2·glyme NiBr2·diglyme Ni(COD)2 NiCl2·glyme NiCl2·glyme NiCl2·glyme
3a 3a 3a 3b 3c 3d 4 5 6 7 5 5 5 5 5
NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP/iPr2O = 7:3 DMA/iPr2O = 7:3 NMP/MeCN = 7:3
6 56 47c 55 55 49 21 65 33 7 68 65 85 71 80
Scheme 2. Coupling of 1 with Other Methyl Sulfonates
a
Reaction conditions: 1 (100 mol %, 0.15 M in NMP), MeOTs (150 mol %), NiCl2·glyme (10 mol %), B2(Pin)2 (200 mol %), ligand (10 mol %), MeOLi (250 mol %), NMP (1 mL). bYields were determined by using GC−MS with 1-tosylpyrrolidine as an internal standard (calibrated). c2.0 equiv of MeOTs.
examination of the ligands, e.g., 3b−d and 4−7, indicated 5 (Figure 1) to be optimal (entries 4−10), generating 2 in 65%
Figure 2. Examples of methylation of various alkyl halides. (a) Isolated yields. (b) Yields were determined by 1H NMR analysis of an inseparable mixture of product and hydrodehalogenation byproduct using PhTMS as internal standard (calibrated). (c) The ratio of product to hydrodehalogenation byproduct was determined by 1H NMR analysis.
Figure 1. Structures of ligands.
yield (entry 8). With ligand 5, other Ni sources were generally inferior, except Ni(COD)2 and NiBr2·diglyme which gave 2 with comparable results (entries 11 and 12). Finally, extensive examination of solvents showed that a mixture of NMP/iPr2O in a ratio of 7:3 is optimal (entries 13−15), which gave rise to 2 in a best 85% yield (entry 13). Under the optimized conditions for 1, the iodo analogue, 4-iodo-1-tosylpiperidine, was less effective and only resulted in 2 in 64% yield. The employment of MeI in place of MeOTs led to a trace amount of product. Under the optimized reaction conditions, coupling of 1 with other sulfonates such as methyl phenylsulfonate, methyl methylsulfonate, and methyl trifluorosulfonate was inferior to MeOTs (Scheme 2). With the optimized reaction conditions being identified (Table 1, entry 13), we examined the scope of secondary and primary alkyl bromides (Figure 2). A variety of cyclic and openchain secondary and primary halides were competent with the
reductive coupling conditions, generally giving methylation products 9−18 in moderate to good yields, where a wide range of functional groups including ester, ketone, indole, phthalimide, and sterically dense 2-TBDPS-protected silyl ether are tolerated. 3-Methyl-1-tosylpyrrolidine 18 was also achieved in moderate yield, where the bromo substrate often suffers from a β-H elimination issue. The unprotected TsNH group underwent methylation on the nitrogen as evident in 19, which consequently resulted in a poor yield for 19. While the sterically more hindered primary alkyl bromides, e.g., 20, gave poor coupling yield, moderate to good yields for the methylation of less hindered primary bromides were generally observed, e.g., in 21−32. Interestingly, the Cbz-protected free amine did not undergo N-methylation as evident in 30. Again, excellent B
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formation of methyl-Zn reagent cannot be excluded, but it should not dominate the reaction process. The reason why MeOTs is suited for methylation is possibly due to relatively slow formation of MeX (X = Cl, Br arising from NiCl2 or alkyl bromides) under the conditions of methylation of alkyl halides and MeI in ketone formation, which avoids rapid dimerization of MeX (X = I, Cl, Br) due to their low concentrations. This hypothesis is in agreement with our previously proposed mechanisms for alkyl− alkyl (Ni/Bpin) and ketone-forming reactions.9b,14 The former case involves oxidative addition of first R1alkyl−X to Ni(I)−Bpin followed by reductive elimination of Bpin−X to give R1alkyl− Ni(I). Subsequent oxidative addition of R2alkyl−X to R1alkyl−Ni(I) gives R1alkyl−Ni(III)− R2alkyl, which delivers the product upon reductive elimination (Scheme 4).14 Successful cross-coupling of
functional group compatibility was observed for methylation of primary alkyl bromides including conjugated alkene as in 27. Similarly, with MeOTs being the methylation reagent, we examined the possibility of methylation of allylic carbonate, aryl bromide, and acid chlorides under the standard conditions developed by our laboratory (Scheme S1, Supporting Information).9b,d,e,15,16 Whereas the allyl and aryl electrophiles failed to generate methylation products (Scheme S1, Supporting Information), 4-Methoxy benzoyl chloride provided the desired ketone product in 27% yield in the presence of Bu4NI (Scheme S1, Supporting Information).16 Extensive optimization of the reaction parameters enabled us to boost the yield to 60% by using 15% of Ni(acac)2, 15% of 5,5′-dimethyl-2,2′-bipyridine (8), and 1.5 equiv of acid chlorides and MgCl2 in THF/CH3CN (v/v, 4:1) (Scheme 3).
Scheme 4. Proposed Catalytic Cycle for Methylation of Alkyl Halides
Scheme 3. Optimized Reaction Conditions for Methylation of 4-Methoxybenzoyl Chloride
Application of the optimized methyl ketone formation conditions to a variety of aryl acid chlorides were explored, generating 33−43. In general, the aryl rings bearing electrondonating substituents displayed better coupling efficiency than those containing electron-withdrawing groups by delivering moderate to good yields as evident in Figure 3. The use of methyl two alkyl halides would require a matched oxidative addition rates for the two coupling partners. Therefore, a low concentration of MeX (X = Cl, Br) should guarantee a low oxidative addition rate for MeX so as to match the oxidative addition rate for a second yet more hindered alkyl halide. Consequently, rapid dimerization of MeX can be avoided. For ketone synthesis, the proposed mechanism suggests that oxidative addition of acid chlorides to Ni(0) needs to be faster than that of MeX.9b A low concentration of MeX (X = I) is therefore pivotal to reduce the oxidative addition rate of MeX to Ni(0). In summary, we have identified methyl tosylate as an excellent methylation reagent for reductive coupling with unactivated alkyl halides and aryl acid chlorides, which allows efficiently installation of a methyl group for alkyl−methyl and ketone formation. The reactions avoid in situ formation of methyl zinc reagents which generally inhibit the reductive coupling process. The easy-to-operate and mild conditions may provide applications for preparation of compounds of interests.
Figure 3. Examples of methylation of various aryl acid chlorides. (a) Isolated yields. (b) Yields were determined by 1H NMR analysis using PhTMS as an internal standard (calibrated).
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4-(chlorocarbonyl)benzoate only resulted in a trace amount of ketone product 44. Finally, the alkyl acid, e.g., 3-phenylpropanoyl chloride, only provided the ketone 45 in low yield. In our previous studies, we have demonstrated that under the Ni/(Bpin)2 reductive coupling conditions in situ formation of alkyl-Bpin followed by Suzuki mechanism is not operative.14 Similarly, we have also illustrated that the coupling of alkyl-Zn reagents with aryl acid chlorides is a slower process than reductive coupling ketone formation.9c,b Indeed, while MeBpin did not give the coupling product, MeZnI was much less effective than MeOTs.16 Consequently, we believe that the present methylation of alkyl halides should not involve in situ formation of methyl-Bpin.17 In the reductive ketone-forming process, the
ASSOCIATED CONTENT
S Supporting Information *
Experimental procedures and analytical data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: [email protected]. *E-mail: [email protected]. Author Contributions §
Z.L. and W.X. contributed equally.
C
dx.doi.org/10.1021/ol502682q | Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters
Letter
Notes
2670. (b) Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674− 688. (c) Hu, X. Chem. Sci. 2011, 2, 1867−1886. (13) For recent reviews on reductive coupling of two electrophiles, see: (a) Knappke, C. E. I.; Grupe, S.; Gärtner, D.; Corpet, M.; Gosmini, C.; von Wangelin, A. J. Chem.Eur. J. 2014, 20, 6828−6842. (b) Everson, D. A.; Weix, D. J. J. Org. Chem. 2014, 80, 4793−4798. (c) Moragas, T.; Correa, A.; Martin, R. Chem.Eur. J. 2014, 20, 8242−8258. (14) Xu, H.; Zhao, C.; Qian, Q.; Deng, W.; Gong, H. Chem. Sci. 2013, 4, 4022−4029. (15) Lu, W.; Liang, Z.; Zhang, Y.; Wu, F.; Qian, Q.; Gong, H. Synthesis 2013, 45, 2234−2240. (16) See the Supporting Information for details. (17) For Ni-, Cu-, and Pd-catalyzed alkyl−Bpin formation, see: (a) Dudnik, A. S.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 10693−10697. (b) Yang, C.-T.; Zhang, Z.-Q.; Tajuddin, H.; Wu, C.-C.; Liang, J.; Liu, J.H.; Fu, Y.; Czyzewska, M.; Steel, P. G.; Marder, T. B.; Liu, L. Angew. Chem., Int. Ed. 2012, 51, 528−532. (c) Ito, H.; Kubota, K. Org. Lett. 2012, 14, 890−893. (d) Joshi-Pangu, A.; Ma, X.; Diane, M.; Iqbal, S.; Kribs, R. J.; Huang, R.; Wang, C.-Y.; Biscoe, M. R. J. Org. Chem. 2012, 77, 6629−6633. (e) Yi, J.; Liu, J. H.; Liang, J.; Dai, J. J.; Yang, C. T.; Fu, Y.; Liu, L. Adv. Synth. Catal. 2012, 354, 1685−1691.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Dr. Hongmei Deng (Shanghai University) is thanked for use of the NMR facility. Financial support was provided by the Chinese NSF (Nos. 21172140 and 21372151) and the Program for Professor of Special Appointment at Shanghai Institutions of Higher Learning (Dongfang Scholar) Shanghai Education Committee.
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